Dynamic interactions betweens stem cells and their niche. This is a second revision of a competitive renewal that focuses on the hematopoietic stem cell under conditions of physiologic stress. The premise underlying this proposal is that the stem cell and its niche are dynamic and modified in function in response to settings of tissue injury. The P2 family of G protein-coupled receptors responds to nucleotides and their conjugates, and also mediates response of immune, vascular and neural cells to tissue damage. They are thought to provide a mechanism for sensing release of intracellular contents from damaged cells. We previously identified P2Y14, the receptor for UDP-glyco-conjugates, on the surface of hematopoietic stem cells. Through the course of the revisions of this proposal, we have now demonstrated that mice genetically altered to be deficient in P2Y14 have an abnormal response to bone marrow injury. This receptor restricts stem cell entry into cycle under stress conditions, protecting stem cells from myelotoxic depletion. Further, depleting P2Y14, enhances stem cell reconstitution of radiation injured bone marrow. Of note, stem cell function under homeostatic conditions are unaffected by P2Y14 deficiency. We plan to pursue study of P2Y14 as a mediator of response to injury at the stem cell level through the following aims: 1. Determine whether P2Y14 alters sensitivity to stress under stem cell autonomous or niche mediated conditions 2. Define the mechanistic basis for the effect of P2Y14 on stem cell function 3. Determine whether leukemic suppression of normal stem cell function is mediated by P2Y14 and whether altering P2Y14 activity can modify the kinetics of leukemic disease. If successful, these studies will define a novel molecular target to influence the function of stem cells in settings of marrow injury.